Glycine is known as an excitatory and inhibitory neurotransmitter in the central and peripheral nervous systems. These functions work via two different types of receptors, in which different types of glycine transporter are independently involved. The function as a inhibitory neurotransmitter works via the strychnine-sensitive glycine receptor present mainly in spinal cord and brain stem. Alternatively, the function as an excitatory neurotransmitter works via N-methyl-D-aspartic acid (NMDA) receptor known as a subtype of glutamate receptors. Glycine is known as a coagonist for the NMDA receptor (Johnson J. W. and Asher P., Glycine potentiates the NMDA response in clutured mouse brain neurons, Nature, 325, 529–531, (1987)). The NMDA receptor is widely distributed in brain, particularly in cerebral cortex and hippocampus.
Neurotransmitter transporter plays a significant role in the control of the concentration of neurotransmitter in the synaptic cleft, by incorporating the neurotransmitter inside the cells. Additionally, it is considered that neurotransmitter transporter makes a contribution to the recycling of neurotransmitter, by incorporating the neurotransmitter into the presynapse terminus. It is considered that the control of the functions of neurotransmitter transporter is useful for therapeutically treating various diseased conditions due to abnormalities in nerve functions, through the control of the concentration of neurotransmitter in the synaptic cleft.
Glycine transporter (GLYT) was first cloned in 1992 (Guastella J., et al., Cloning, expression and localization of a rat brain high-affinity glycine transporter, Proc. Natl. Acad. Sci., 89, 7189–93, 1992). Two types of the transporters, namely GLYT1 and GLYT2, have been identified so far (Liu Q. R., et al., Cloning and expression of a spinal cord- and brain-specific glycine transporter with novel structural features, J. Biol. Chem., 268, 22802–8, 1993). Furthermore, a report tells that GLYT1 has several splicing variants (Kim K. M., et al., Cloning of the human glycine transporter type 1: molecular and pharmacological characterization of novel isoform variants and chromosomal localization of the gene in the human and mouse genomes, Mol. Pharmacol., 45, 608–17, 1994).
GLYT1 is expressed at a high density in spinal cord, brain stem, cerebellum, diencephalon and retina, while GLYT1 is expressed at a low density in olfactory bulb and cerebral hemisphere. It is considered that GLYT1 controls the NMDA receptor function (Smith K. E., et al., Cloning and expression of a glycine transporter reveal colocalization with NMDA receptors, Neuron, 8, 927–35, 1992; Guastella J., et al., Cloning, expression, and localization of a rat brain high-affinity glycine transporter, Proc. Natl. Acad. Sci., 89, 7189–93, 1992; and Bergeron, R., et al., Modulation of N-methyl-D-aspartate receptor function by glycine transport, Proc. Natl. Acad. Sci. USA, 95, 15730–15734, 1998). Javitt, et al. have reported that glycyldodecylamide (GDA) as a glycine transporter inhibitor suppresses the enhancement of activity in mouse as induced by phencyclidine (PCP) as an NMDA receptor antagonist (Javitt D. C., et al., Reversal of phencyclidine-induced hyperactivity by glycine and the glycine uptake inhibitor glycinedodecylaminde, Neuropsychopharmacology, 17, 202–4, 1997).
Alternatively, the expression of GLYT2 is limited to spinal cord, brain stem and cerebellum (Goebel D. J., Quantitative gene expression of two types of glycine transporter in the rat central nervous system, Mol. Brain Res., 40, 139–42, 1996; Zafra F., et al., Glycine transporters are differentially expressed among CNS cells, J. Neurosci., 15, 3952–69, 1995). Thus, it is considered that GLYT2 is involved in the control of the function of strychnine-sensitive glycine receptor. It is suggested that the inhibition of GLYT2 induces the attenuation of pain transmission in spinal cord via the enhancing action of strychnine-sensitive glycine receptor function (Yaksh, T. L., Behavioral and autonomic correlates of the tactile evoked allodynia produced by spinal glycine inhibition: effects of modulatory receptor systems and excitatory amino acid antagonists, Pain, 37, 111–123, 1989).
Furthermore, the enhancement of the strychnine-sensitive glycine receptor function is useful for the therapeutic treatment of abnormal muscular constraction such as spasm, myoclonus and epilepsy (Truong D. D., et al., Glycine involvement in DDT-induced myoclonus. Movement Disorders. 3,77–87, 1988; and Becker, C. M., et al., Disorders of the inhibitory glycine receptor: the spastic mouse, FASEB J. 4, 2767–2774, 1990). Spasm has a relation with nerve disorders and damages such as epilepsy, cerebrovascular disorders, head injuries, multiple sclerosis, spinal injuries and dystonia.
It has been known that NMDA receptor has relations with various diseased conditions. It is suggested that the functional deterioration of NMDA receptor has a relation with schizophrenia (Javitt D. C. and Zukin S. R., Recent advances in the phencyclidine model of schizophrenia, American Journal of Psychiatry, 148, 1301–8, 1991). It is reported that the negative symptoms of schizophrenic patients are ameliorated with a high dose of glycine (Heresco-Levy U., et al., Double-blind, placebo-controlled, crossover trial of glycine adjuvant therapy for treatment-resistant schizophrenia, Br J Psychiatry, 169, 610–7, 1996).
Additionally, the activation of NMDA receptor is involved in the formation of long-term potentiation (LTP) considered as a memory and learning model at the neuron level (Collingridge G. L. and Bliss T. V., NMDA receptors-their role in long-term potentiation. Trends. Neurosci., 10, 288–93, 1987). Still additionally, the administration of an NMDA receptor antagonist to animals induces an amnesia therein (Morris R. G., Andersen E., Lynch G. S. and Braudy M., Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5, Nature, 319, 774–6, 1986; and Mark J. Benvenga and Theodore C. Spaulding, Amnesic effect of the novel anticonvulsant MK-801, Pharmacol Biochem Behav., 30, 205–207, 1988). Hence, it is suggested that NMDA receptor plays a very significant role in memory and learning.
Further, the deterioration of the function of NMDA receptor has been reported even in humans, namely in patients with Alzheimer-type dementia (Ninomiya, H., et al., binding in human frontal cortex: decreases in Alzheimer-type dementia., J. Neurochem., 54, 526–32, 1990; and Tohgi, H., et al., A selective reduction of excitatory amino acids in cerebrospinal fluid of patients with Alzheimer type dementia compared with vascular dementia of the Binswanger type., Neurosci. lett., 141, 5–8, 1992).
Alternatively, a number of papers report an anti-amnesia action of a glycine-site agonist in animal models (Matsuoka N. and Aigner T. G., D-Cycloserine, apartial agonist at the glycine site coupled to N-methyl-D-aspartate receptors, improves visual recognition memory in rhesus monkeys, J. Exp. Pharmacol. Ther., 278, 891–7, 1996; Ohno M., et al. Intrahippocampal administration of a glycine site antagonist impairs working memory performance of rats. Eur. J. Pharmacol., 253, 183–7, 1994; and Fishkin R. J., et al., D-cycloserine attenuates scopolamine-induced learning and memory deficits in rats., Behav. Neural. Biol., 59, 150–7, 1993). These findings suggest that drugs inhibiting the activity of glycine transporter and thereby activating the function of NMDA receptor are useful as therapeutic agents of dementia, schizophrenia and other cognitive disorders.
As the glycine transporter inhibitor, WO97/45115 disclosing tertiary amins and WO97/45423 disclosing piperidine derivatives (TROPHIX PHARMACEUTICALS INC.), WO99/34790 disclosing amino acid derivatives and WO99/41227 disclosing tricyclic compounds (ALLELIX NEUROSCIENCE INC.), WO99/44596 and WO99/45011 disclosing piperidine derivatives (JANSSEN PHARMACEUTICA N.V.), and WO00/07978 disclosing aminomethylcarbonate derivatives (AKZO NOBEL N.V.) are reported, other than glycyldodecylamide (GDA). As 1,2,4-triazole derivatives, the following compounds are disclosed: DE4302051 (Dr. Karl Thomae G.m.b.h., platlet aggregation inhibitory activity; Iran. J. Chem. Chem. Eng. (1998), 17, 14 (A. Shafiee, et al., antibacterial and antifungal activities), DE3808283 (Boehringer Ingelheim K G., platelet activation factor antagonistic activity), WO97/32873 (Pfizer Research and Development Company N.V., NMDA receptor antagonistic activity), and DD251345 (VEB Chemiekombinat Bitterfeld Ger. Dem. Rep., biocidal activity), Eur. J. Med. Chem. (1985), 20, 257(F. Clemence, et al., analgesic and anti-inflammation activity), Sci. Pharm. (1978), 46, 298 (A. A. B. Hazzaa, et al., anti-spasm action). However, there are no reports that these compounds inhibit glycine transporter activity.
Based on the background described above, the present inventors have made investigations about compounds with potent inhibitory activity of glycine transporter. Consequently, the inventors have found that a specific type of triazole derivative has a potent inhibitory activity of glycine transporter. Thus, the invention has been achieved.